RU2473346C1 - Method of treating drug-induced liver injury in children suffering from tuberculosis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: declared invention refers to medicine. The anti-tuberculosis preparations are cancelled, while Ursosal 20 mg/kg is single administered per os, and Enterosgel 10-15 g for 3 days. Then, a dose of Ursosan is reduced to 12-15 mg/kg a day with underlying reinitiation of the anti-tuberculosis preparations, and the Ursosan therapy is continued until the ALT value appears to be below an upper limit of normal.

EFFECT: method under invention enables higher clinical effectiveness in the drug-induced liver injury in children.

1 tbl, 3 dwg, 2 ex

Description

The invention relates to medicine, namely to phthisiology, and may find application in the treatment of drug-induced liver damage in children (LIPP).

There is a method of treating toxic hepatitis with the appointment of basic therapy (gentle regimen, hepatic diet, drinking 5% glucose solution) and currently used lipotropic and membrane-stabilizing preparations containing milk thistle (legal, carlsil, etc.) or essential phospholipids (essentials). The disadvantage of this known method is that the proposed drugs have age restrictions in their purpose and duration of administration. This therapy often does not provide a tangible increase in the antitoxic function of the liver. In addition, these hepatoprotective drugs in some patients can contribute to an increase in cholestasis (Stepanov Yu.M., Filippova A.Yu., Kononov I.N. Medicinal liver lesions: pathogenesis, classification, diagnosis, treatment // J. "Pharmacist", 2005, No. 5. Okovyty SV Clinical pharmacology of hepatoprotectors // Practitioner, 2002. - No. 3).

The objective of the invention is to increase the effectiveness of the treatment of drug-induced liver damage in children with pulmonary tuberculosis.

The problem is solved in a way that patients are discontinued taking anti-TB drugs and orally administered ursosan at a dose of 20 mg / kg once and enterosgel 10-15 g for 3 days, then reduce the dose of ursosan to 12-15 mg / kg per day in 2-3 doses and enterosgel in age dosages against the background of the resumption of taking anti-tuberculosis drugs and are treated with ursosan to the value of alanine aminotransferase (ALT), not exceeding the upper limit of normal.

Tuberculosis chemotherapy was usually carried out with 4 anti-TB drugs (PTP) - isoniazid, rifampicin, pyrazinamide and streptomycin or ethambutol in age dosages.

Ursosan is a drug of ursodeoxycholic acid (UDCA).

UDCA is a tertiary non-toxic bile acid, which in the human body is formed endogenously. It is synthesized from 7-ketolitocholic acid, a product of the bacterial oxidation of chenodeoxycholic acid. UDCA is more polar and hydrophilic than other bile acids, which excludes the possibility of formation of micelles toxic to liver cells (Vidal Handbook “Medicines in Russia”, 1999).

Enterosgel - a drug from the group of sorbents, being in the intestinal lumen, interrupts the circulation of toxic metabolites and other substances, thereby reducing the toxic and metabolic load on the body and liver. Enterosgel has several advantages compared to sorbents of a different nature: due to its hydrophobicity, it is rapidly excreted from the gastrointestinal tract together with toxic substances and practically does not penetrate the internal environment of the body through the intestinal barrier (Vidal Handbook “Medicines in Russia”, 1999).

The following LIPP criteria were used (EASL Clinical Practive Guidelines: Management of cholestatic liver diseas // J. of Hepatology. - 2009. - No. 51 - P.237-267): the presence of laboratory signs of liver damage (increase in the level of total bilirubin more than 20 μmol / l, direct bilirubin more than 4 μmol / l, increased liver transaminase activity over 40 units / l); the presence of a temporary connection with the use of anti-TB drugs; the exclusion of other causes of liver damage.

Under observation were 114 tuberculosis patients with LIPP for children aged 3 to 17 years.

Of these: 39 children made up the main group receiving the proposed treatment: orally ursosan at a dose of 20 mg / kg once and enterosgel 10-15 g for 3 days, then reduced the dose of ursosan to 12-15 mg / kg per day in 2-3 intake and enterosgel in age dosages against the background of the resumption of taking anti-TB drugs and were treated with ursosan to a ALT value that does not exceed the upper limit of the norm.

The control group consisted of 38 children who were treated in the generally accepted way: basic therapy in combination with Karsil, or Hofitol, or Essential in recommended doses by age.

Clinical examples

1. N-gu Cristina, 11 years old, history No. 165/5471. I was treated in the children's tuberculosis department from 02/08/2008 to 08/18/2008 with a diagnosis of Infiltrative tuberculosis of the upper lobe of the right lung C2, C3, C6 in the decay phase. Office (+). Upon receipt of a biochemical blood test within normal limits: total. beat. - 8.1 μmol / l, straight. beat. - 2.8 μmol / L, ALT - 12.7 units / L, ACT - 17.9 units / L. Hepatitis B and C virus markers are negative.

Antituberculous therapy was prescribed with 4 drugs, including rifampicin, in age dosages. On the 14th day of treatment, nausea, vomiting, headache, and abdominal pain appeared. On examination: skin of normal color, sclera subicteric; the stomach is painful in the right hypochondrium, the liver protrudes from the edge of the costal arch by 1.5-2 cm. The chair is of a normal color. In the biochemical analysis of blood - an increase in total bilirubin to 26.4 μmol / L, direct bilirubin - up to 12.0 μmol / L, ALT - 513.2 units / L, asparagintransferase (ACT) - 374.8 units / L. Apoptosis of peripheral blood lymphocytes (LPC) - 1.58% (normal - 0.7%). Ultrasound of the abdominal organs marked hepatomegaly, increased liver echogenicity. The patient was exposed to LIPP with pronounced cytolysis syndrome, moderate cholestatic syndrome. Treatment: PTP was canceled, ursosan was administered orally at a dose of 20 mg / kg once and enterosgel 10 g for 3 days, then the dose of ursosan was reduced to 15 mg / kg per day in 2-3 doses and enterosgel at age dosages against the background of the resumption of anti-tuberculosis drugs and were treated with ursosan to a ALT value that did not exceed the upper limit of the norm.

Against the background of the therapy, for 3 days the symptoms of intoxication and dyspeptic symptoms were stopped, the liver protrudes 1 cm from the edge of the costal arch, is sensitive. The biochemical blood test completely normalized after 21 days: total bilirubin - 16.4 μmol / l, direct bilirubin - 2.89 μmol / l, ALT - 19.5 units / l (does not exceed the upper limit of the norm), ACT - 32, 4 units / l. Apoptosis LPK - within normal limits - 0.7%.

2. Child L-new Oleg, 13 years old; History No. 1394/42529. He was treated in the children's tuberculosis department from 12/01/2008 to 07/10/2009 with a diagnosis of Right-sided exudative pleurisy of tuberculous etiology. Office (-). On admission: a biochemical blood test within normal limits: total bilirubin - 20.9 μmol / l, direct bilirubin - 6.5 μmol / l, ALT - 43.5 units / l, ACT - 35.9 units / l. Hepatitis B and C virus markers are negative. Prescribed anti-tuberculosis therapy with 4 drugs, including rifampicin, in age dosages. After 10 days from the start of therapy, complaints of weakness, nausea, vomiting, and decreased appetite appeared. On examination, the skin is of normal color, the abdomen is soft, sensitive to palpation in the right hypochondrium, the liver protrudes 1.5 cm from the edge of the costal arch. The spleen is not palpable. Ultrasound of the abdominal organs marked hepatomegaly, increased liver echogenicity. In the biochemical analysis of blood: total bilirubin - 21.4 μmol / L, an increase in direct bilirubin to 9.77 μmol / L, an increase in transaminases: ALT - 492.6 units / L, ACT - 539.8 units / L. Apoptosis of the LPC was 0.83% (normal - 0.7%). LIPP was diagnosed with mild cholestasis syndrome and severe cytolysis syndrome. Rifampicin was canceled in the treatment, basic therapy and heptral were prescribed 1 t. × 2 times (2 weeks), then essential 1 to 3 times a day. Against the background of the therapy, the normalization of biochemical parameters - ALT - occurred only after 30 days. On examination, the skin and sclera of normal color, the abdomen is soft, painless, the edge of the liver is palpated, painless palpation. After 3 months from the start of treatment, the child showed a negative radiological dynamics in the form of an increase in the amount of pleural effusion. Against the background of increased anti-tuberculosis therapy, a relapse of LIPP with a cytolytic syndrome was noted: total bilirubin - 14.0 μmol / L, direct - 3.46 μmol / L, ALT - 180.4 units / L, ACT - 182.6 units / L . In dynamics, along with the deterioration of clinical and laboratory parameters, there was a further decrease in the level of apoptosis - LPC to 0.1, which could adversely affect not only LIPP, but also tuberculosis.

As a result, the child noted slower clinical and radiological dynamics - the development of armor pleurisy with a sharp restriction of the mobility of the diaphragm, which required surgical treatment.

Analysis of treatment results in the main and control groups on the dynamics of ALT showed (table 1) that the proposed method of treatment provides a more rapid decrease in ALT. When compared by day, the ALT normalization time in children of the main group was almost half that in patients in the control group (29.6 ± 4.8 and 49.6 ± 5.7 days, respectively, p≤0.013). The data show a significant decrease in the duration of toxic changes in the liver in children receiving ursosan and enterosgel according to the proposed method, which allows a more rapid resumption of full chemotherapy for tuberculosis.

In addition, in the course of the study, it was found that, with the use of ursosan, an improvement in the apoptosis of peripheral blood lymphocytes (LPC) in children with tuberculosis occurs significantly more often than with standard therapy for both cholestasis syndrome and cytolysis syndrome (p = 0.049 and p = 0.004) (Fig. 1, 2).

Thus, the proposed method for the treatment of LIPP in children with tuberculosis allows: to reduce by 1.6 times the normalization of liver function (by the ALT enzyme) and restore an adequate regimen of chemotherapy for tuberculosis; in addition, normalize the apoptosis of peripheral blood lymphocytes, which favorably affects the course of not only LIPP, but also tuberculosis in general.

It was also shown that the anticholestatic effect was significantly more pronounced when taking ursosan than with basal therapy: an increase in cholestasis against the background of continued PTP in the main group treated with ursosan was significantly less likely than with basal therapy (14.7% versus 50, 0%, p = 0.029) (Fig. 3).

Claims (1)

A method for the treatment of drug-induced liver damage in children with pulmonary tuberculosis, which consists in the fact that patients are discontinued taking anti-TB drugs and orally administered ursosan at a dose of 20 mg / kg, once and enterosgel 10-15 g for 3 days, then reduce the dose of ursosan to 12-15 mg / kg per day against the background of the resumption of taking anti-TB drugs and conduct therapy with ursosan until the ALT value does not exceed the upper limit of the norm.

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